Measuring and testing – Volume or rate of flow – By measuring transit time of tracer or tag
Reexamination Certificate
1999-12-21
2002-05-14
Patel, Harshad (Department: 2855)
Measuring and testing
Volume or rate of flow
By measuring transit time of tracer or tag
C073S861070, C073S204140
Reexamination Certificate
active
06386050
ABSTRACT:
TECHNICAL FIELD
The invention relates generally to systems and methods for measuring low volume flows of liquid and relates more particularly to non-invasively measuring flow rates within liquid analysis systems and drug delivery systems that require a high degree of flow measurement accuracy in extremely low volume applications.
BACKGROUND ART
Accurate measurements of low volumetric liquid flow rates are important in many analytical applications, such as flow injection analysis, micro-bore liquid chromatography, capillary chromatography, capillary electrophoresis, and bioassay applications. Precise measurements are also important in drug delivery applications. The flow rate in analytical systems may be in the range of 0.0001 milliliter/minute (ml/min) to 1 ml/min. In medical applications, the flow rate may be as low as 0.008 ml/min for ambulatory infusion. In addition to accuracy, other concerns in selecting an approach for measuring flow rate include providing a fast dynamic response and minimizing the risk of introducing contamination into the flow of liquid.
The most common approaches to measuring flow rate incorporate a heater and at least one temperature-sensitive resistor within the flow channel. In a thermal transit-time approach, the heater is supplied with a signal, such as a square-wave voltage at a selected frequency, to inject heat pulses as tracers into the fluid of interest. The periodic heat tracers travel along the flow channel, causing periodic temperature fluctuations downstream. The heat tracers are detected by a thermistor or other temperature sensing device that is located within the flow. In steady state, the phase shift of the downstream thermal fluctuations relative to the upstream thermal fluctuations are related to the mean velocity of the fluid. This approach has little dependency on the ambient temperature and on the properties of the liquid, so that the transit time can be determined accurately.
In a thermal dilution flow approach, three resistors may be located along a flow channel, with the center resistor being used as the heater and the end resistors being used as temperature-sensitive members. Current is passed through the heater to trigger a change in temperature within the liquid flow. The two temperature-sensitive resistors are located equidistantly from the heater resistor and are used to sense the heat distribution from the center. Flow rate is determined as a function of the temperature difference between the upstream and downstream temperature-sensitive resistors.
One approach that does not utilize temperature-sensitive members is the differential pressure flow approach. In laminar flow conditions with low Reynolds numbers, the pressure difference across an orifice is proportional to the flow rate.
There are a number of concerns with these conventional approaches to determining flow rate. A first concern is that contact with the flowing liquid will introduce contamination into the stream. A contamination-free approach to determining flow rate is important in chemical analysis applications and drug delivery applications. Another concern is that the approaches may not be sufficiently sensitive at extremely low flow rates.
Systems for measuring liquid flow rates without contacting the liquid are described in U.S. Pat. No. 5,764,539 to Rani and U.S. Pat. No. 4,938,079 to Goldberg. In Rani, a pump is operated to deliver a fluid in pulses. The fluid flows through a fluid delivery tube. A sensor is in contact with the outer surface of the fluid delivery tube in order to detect the temperature of the outer surface. The sensor is calibrated at an initial temperature and is responsive to the flow of fluid through the tube. Since fluid flow will increase the temperature at the outer surface of the tube, the output of the temperature-sensitive sensor is indicative of the flow rate through the tube. While the Rani system may operate as designed, the sensitivity of the measurements may not be sufficient at the flow rates associated with many analytical systems and medical applications. Moreover, the pulsed deliveries may not be desirable in many applications.
The Goldberg system utilizes microwave energy to determine flow rates. A thermal marker is introduced into the flow of liquid to be measured. For example, a heat pulse may be generated by radiating energy into the stream using a microwave heating device. An alternative means of introducing the thermal marker is through the use of focused infrared energy produced by a laser or other source. The flow rate may be measured by determining the transit time of the thermal marker from the heater to a sensor. In the preferred embodiment, the liquid conduit is passed through a resonant microwave cavity such that the resonant characteristics of the cavity are affected by the passage of the thermal marker. For example, the dielectric constant of the liquid will change with temperature, so that the resonant frequency of the microwave cavity will vary with passage of the thermal marker through the cavity. The Goldberg system is designed to provide accuracy at flow rates below 100 cc/hour. However, the use of microwave signals limits the sensitivity of the system. As a consequence, the Goldberg system is not easily adapted to use in micro fabricated devices and micro analysis systems.
U.S. Pat. No. 5,726,357 to Manaka and U.S. Pat. No. 5,623,097 to Horiguchi et al. describe micro fabricated devices which employ the thermal approaches described above. Thus, the flow sensors are highly sensitive, but directly contact the flowing fluid. In Manaka, a substrate is patterned to include a heating portion and a sensing portion. The transit time for heat transfer from the heating portion to the sensing portion is used to calculate flow rate. Similarly, the Horiguchi et al. sensor includes a substrate through which a fluid path is formed. A bridge is suspended over the fluid path. A heating resistor and a temperature sensor are formed on the bridge through an interlayer isolating film that is designed to eliminate the difference between the temperature of the heater and the heat sensor. A temperature compensating circuit may be used to offset any remaining effects of thermal communication between the heater and the temperature sensor.
While known approaches operate as designed, what is needed is a system and a method for monitoring fluid flow in a manner that does not introduced contamination into the flow and that is easily adapted to applications having a small cell volume.
SUMMARY OF THE INVENTION
A system for measuring flow rate within a fluid-bearing passageway includes introducing a heat tracer into the flow and includes non-invasively and indirectly monitoring the effects of the heat tracer as it propagates to one or more interrogation regions. Typically, the heat tracer is one thermal fluctuation introduced by a modulating heat generator. In one embodiment, the non-invasive monitoring occurs optically. In another embodiment, the electrical conductivity of the fluid is monitored. Based upon the detection of changes in the physical properties of the fluid that propagates through interrogation regions, the rate of flow of the fluid is identified. For example, the phase shift between the modulations of the heat generator and the modulations of temperature-dependent physical properties (optical or electrical) may be used to determine flow rate.
In any of the embodiments, the heat tracer may be introduced using an optical heat generator. For example, the heat generator may include an infrared laser, infrared lamp or a light emitting diode (LED) that generates a beam that is incident to the flow of fluid through a capillary or a micro channel of a micro analytical device. In an alternative embodiment, the heat generator is a coil that is in thermal communication with the passageway, but is removed from direct contact with the fluid.
At least one temperature-dependent property of the fluid is measured upstream of the heat generator, downstream of the heat generator, or both. Thus, the temperature of the fluid is not d
Templin Catherine
Yin Hongfeng
Agilent Technologie,s Inc.
Patel Harshad
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